ORGANIC LETTERS
Synthesis of D-Hexos-5-uloses by Novel in Situ Hydrolysis of Epoxides Derived from 6-Deoxyhex-5-enopyranosides
2000 Vol. 2, No. 24 3929-3932
Philomena M. Enright,† Kathy M. O’Boyle,‡ and Paul V. Murphy*,† Departments of Chemistry and Pharmacology, Conway Institute of Biomolecular and Biomedical Research, UniVersity College Dublin, Belfield, Dublin 4, Ireland
[email protected] Received October 10, 2000
ABSTRACT
Epoxides derived from 2,3,4-tri-O-protected-6-deoxyhex-5-enopyranosides are hydrolyzed in situ to ultimately give novel protected-D-hexos5-ulose derivatives (sugar 1,5-dicarbonyls, 5-ketohexoses) in moderate to high yields. The products adopt a bicyclic structure (1,6-anhydropyranos5-ulose) in solution with the pyranose ring in 4C1 conformation. The methodology has been used to prepare D-xylo-hexos-5-ulose (5-ketoglucose), a synthetic precursor to 1-deoxynojirimycin and a possible intermediate in the biosynthesis of inositols.
Our interest in the synthesis of novel glycosaminoglycan derivatives1 and other carbohydrates for biological evaluation prompted us to study the synthetic potential of epoxides 1. We envisaged that reactions of these compounds with reducing reagents or nucleophiles could proceed in a diastereoselective and/or regioselective manner to give idopyranosides and their analogues (Scheme 1). These intermediates could be further elaborated into iduronic acid glycosyl donors, novel aminoglycosides with potential as RNA binding agents,2 or other glycomimetics.3 Recent interest has focused on the synthetic potential of carbohydrate epoxides that are intermediates used in the preparation of oligosaccharides and other carbohydrate derivatives.4 6-Deoxyhex5-enopyranosides have proven to be useful intermediates in †
Department of Chemistry. Department of Pharmacology. (1) Lander, A. D. Chem. Biol. 1994, 1, 73. (2) Alper, P. B.; Hendrix, M.; Sears, P.; Wong, C.-H. J. Am. Chem. Soc. 1998, 120, 1965. (3) Wong, C.-H. Acc. Chem. Res. 1999, 32, 376. (4) (a) Seeberger, P. H.; Bilodeau, M. T.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380. (b) Nicotra, F.; Panza, L.; Russo, G. Tetrahedron Lett. 1991, 4035. (c) Alcaraz, M.-L.; Griffin, F. K.; Paterson, D. E.; Taylor R. J. K. Tetrahedron Lett. 1998, 39, 8183. ‡
10.1021/ol006714w CCC: $19.00 Published on Web 11/03/2000
© 2000 American Chemical Society
synthesis. They can be used, for example, to prepare carbacycles by the Ferrier and other rearrangement reactions.5 However, little work has been reported on the synthesis and reactions of their epoxides.6 We now describe our preliminary results, which show that these epoxides are readily hydrolyzed to give novel D-hexos-5-ulose (5-ketohexose) derivatives. Synthetic routes to the glycals 3 and 4 are well established,7 and the sequence used for their preparation was adapted from these methods (Scheme 2). The preparation
Scheme 1
in situ,12 giving 6 consistently in yields greater than 75%; this reaction can easily be carried out on a multigram scale.13 The yields of ketohexose 6 were reduced when other conditions were employed. The formation of the products obtained can be explained by a mechanism that involves hydrolysis of the initially formed epoxide 2, giving the hemiacetal 7 that subsequently loses methanol (Scheme 3).
Scheme 2a
Reagents and conditions: (a) PPh3, Im, I2, toluene, 80 °C, 3 h; (b) TMSCl, Py, 25 °C; (c) DBU, DMF, 70 °C, 3 h; (d) Ac2O, Py; (e) NaOMe, MeOH, 25 °C, 12 h; (f) NaH, BnBr, DMF, 0 °C, 15 h.
Scheme 3
a
of 3 can be carried out without purification of the intermediates. Thus, methyl 6-iodo-6-deoxy-R-D-glucopyranoside was prepared as described previously from methyl R-D-glucopyranoside8 and then treated with excess TMSCl in pyridine to give 2. This protected iodide was converted to glycal 3 by the elimination of hydrogen iodide9 and exchange of the TMS groups for acetates. Deacetylation and benzylation gave 4.10 D-Hexos-5-ulose derivatives 5 and 611 were respectively obtained when 3 and 4 were subjected to a variety of epoxidation conditions (Table 1).
Table 1. Epoxidation-Hydrolysis of 3 and 4
entry
R
reagents and conditionsa
% yield
1 2 3 4 5 6 7 8 9
Bn Bn Bn Bn Bn Bn Ac Ac Ac
a b c d e f a b d
35 30 26 75-95 43 26
